The gastrointestinal (GI) tract in humans refers to the stomach and the intestine and sometimes to all the structures from the mouth to the anus. The upper gastrointestinal tract consists of the esophagus, stomach and duodenum. Some sources also include the mouth cavity and pharnyx. The exact demarcation between “upper” and “lower” can vary. Upon gross dissection, the duodenum may appear to be a unified organ, but it is often divided into two parts based upon function, arterial supply, or embryology. The integrated part of GI tract is pancreas and liver named the accessory organs of GI tract.
The lower gastrointestinal tract includes most of the small intestine and all of the large intestine. According to some sources, it also includes the anus. The intestine—or bowel—is divided into the small intestine and the large intestine. The small intestine has three parts: i) duodenum where the digestive juices from pancreas and liver mix together, ii) jejenum which is the midsection of the intestine, connecting duodenum to ileum and iii) ileum which has villi in where all soluble molecules are absorbed into the blood. The large intestine also has three parts: i) cacum where the vermiform appendix is attached to the cecum, ii) colon which consists of the ascending colon, transverse colon, descending colon and sigmoid flexure, and iii) rectum.
The intestine has two main roles: digestion and absorption of nutrients, and maintenance of a barrier against the external environment. It also forms the largest endocrine organ in the body as well as the largest and most complex part of the immune system.
In human adults the intestinal surface area is large, about 100 m2. This large area is continuously exposed to different antigens in the form of food constituents (the adult human encounter 12.5 kg of pure protein/year), normal intestinal microflora and pathogens.
The intestinal mucosal surface is lined by a single layer of epithelial cells (IEC) which are continuously and rapidly replaced by replication of undifferentiated cells within the crypt (7×106 cell/min). The epithelial cell layer of the intestinal mucosa is very complex and unique. It secrets digestive enzymes from the apical part to lumen for food digestion. It also secretes different proteins from the second half to the lamina properia (LP).
Further, said epithelial cells are receiving signals from both the lumen (and then transmitting the information to the diverse populations of cells in the LP) and the basolateral side. On the basolateral side the intestinal epithelial cells (IECs) receive many signals from various immune cells, nerve cells and stromal cells. Signals on both sides are affected by their respective microenvironments, influencing the functional states, behaviours, and structures of enterocytes resulting in integrity and homeostasis of the gastrointestinal tract (5).
One divides the postnatal development of the intestines into different phases: early suckling (change from amniotic fluid to colostrum), suckling (change from colostrum to milk), weaning (change from liquid diet, milk, to solid feed) and adulthood (adaptive changes due to diet variation) (Walthal K, et al., Birth Defects Research, 2005, part B, 74:132-156, review). Thus, by manipulating the condition on one side of the epithelial cell layer of the intestinal mucosal surface, the process of postnatal development of gut—including the intestine—could be accelerated or delayed. Past research has confirmed the possibility of accelerating the rate of gut maturation by using exogenous material like PHA (Radberg K, Biernat M, Linderoth A, Zabielski R, Pierzynowski S G & Westrom B R (2001) Enteral exposure to crude red kidney bean lectin induces maturation of the gut in suckling pigs. J Anim Sci 2001; 79:2669-2678) and IL-2 (Peulen O, Dandrifosse G. Spermine-induced maturation in Wistar rat intestine: a cytokine-dependent mechanism. J Pediatr Gastroenterol Nutr 2004, 38:524-532), but at present it is not known in detail as to which types of compounds that could induce fast acceleration.
Mammals are born with intestine that is not fully mature. Depending on the species, the complete maturation varies, but it is always achieved during the weaning period indicating that for the first couple of weeks all mammals haven an immature intestine. In rats, for example, the complete maturation coincides with the dietary shift from milk to solid food. Simultaneous with the onset of the maturation process, changes in the function and architecture of the epithelial cells in the intestine are seen as well as in the weight of the organs, the latter, of which is increasing in most mammals. Such functional and architectural markers are used to identify and measure the onset of the gut and intestinal maturation.
Investigation of gut development is quite a challenge. However, it is an attractive objective for many researchers in gastrointestinal area due to the fact that immature intestine and intestinal diseases are interrelated. In humans, for example, necrotizing enterocolitis (NEC) is the most common gastrointestinal problem in the neonatal intensive care unit (NICU). NEC syndrome is characterized by rapid necrotic death of intestine, involving 75% or more of total length of jejunum, ileum and colon. Development of NEC relates to maturity of gastrointestinal tract and up to 90% of cases refer to preterm born babies. The more preterm the infant is, the higher risk for NEC, and unfortunately, no non-surgical treatment for this syndrome is officially reported. Therefore, NEC-related morbidity remains unchanged over the past 50 years. First described over a century ago necrotising enterocolitis (NEC) is now the most common gastrointestinal emergency occurring in neonates. It is an acquired disorder with a mortality as high as 50% (10-44% in infants less than 1500 g, 0-20% in infants over 2500 g). Prematurity and low birthweight are the most important risk factors. Average yearly infant death rate from NEC has been reported as 12.4 deaths per 100,000 live births with an incidence of 0.5 to 5 patients per 1000 live births. NEC is characterized by an immature gastrointestinal tract and high mucosal permeability to antigen leading to systemic shock and rapid death in some cases (Kosloske, A. M. Epidemiology of necrotizing enterocolitis. Acta Paediatr. Suppl. 1994; 396:2-7).
At present, there are a very limited number of therapies known of a condition originating form an immature gastrointestinal tract such as e.g. necrotizing enterocolitis. Further, it is desirable to use less toxic substances, particularly in newborns. PHA (phytohaemagglutinin), which has previously demonstrated effects on intestinal maturation, such as induction of mitosis, increase in cell membrane permeability and transport across a membrane, is a lectin found in plants, especially legumes. The substance has a number of physiological effects and is used in medical research. In high doses, however it is a toxin. As a toxin, it can cause poisoning.
IL2 is an interleukin normally produced by the body during an immune response. IL-2 is also necessary during T cell development in the thymus for the maturation of subsets of T cells.
It may thus be less favorable to use PHA or IL2 in infants with gastrointestinal problem in a neonatal intensive care unit.
There is thus an urgent need to develop novel therapies and prevent disease such as necrotizing enterocolitis, particularly in newborn. Thus, understanding gastrointestinal development and particularly maturation of the small intestine is of great importance in newborns. Accordingly, the present invention seeks to provide means and methods to address such needs and interests.